Oxygen efficient respiratory Aid (OxEraTM) device: A safety study

African relevance • Africa is a continent that has many developing countries that have constant strain on their healthcare systems.• Now with the COVID pandemic, the use of oxygen and need for cost efficient and safe oxygen devices has increased.• OxEraTM is an oxygen delivery device that has been designed and developed by a consortium named Umoya for emergency use (approval from SAPHRA) in the COVID 19 pandemic.• Given the potential for the widespread utilisation of this oxygen device in a resource-limited setting, we performed a clinical assessment safety study.

Another important challenge related to positive pressure ventilation delivered through a non-invasive device relates to patient comfort and acceptance [6] . The ability of a patient to tolerate the device is therefore vital to the utility of such a device and necessitates the objective assessment of pain and discomfort. Pain and discomfort are notoriously difficult to assess in severe or critically ill patients [7] . Appropriate assessment of pain is key to its management [8] . Tracking physiological parameters including HR and blood pressure together with the use of validated pain tools like the Numerical Rating Scale (NRS) and the Visual Analogue Scale (VAS) are required to objectively assess comfort and pain [9] .
Given the obvious potential for the widespread utilisation of this oxygen device in a resource-limited setting we performed a clinical assessment study. To evaluate the safety and patient acceptance of the OxEra TM device, we evaluated the device on a group of healthy volunteers and monitored ETCO 2 , oxygen saturation, physiological variables related to pain, and we performed an objective pain assessment using three different pain and comfort tools.
The aim was to assess the safety and user acceptance of the OxEra TM device using a healthy volunteer population. The primary objective was to monitor for an increase in ETCO 2 (less than 6.3 mmHg change from baseline ETCO 2 and no ETCO 2 above the 45 mmHg threshold). The secondary objective was to monitor changes in vital signs (maintenance of normal pulse oximetry saturation readings (above 93%) and changes in blood pressure, mean arterial pressure, respiratory rate, and HR). The tertiary objective was pain and comfort score assessment (using the OxEra TM at each time interval with varying PEPs).

Methods
Study Design and Setting: We performed an experimental safety study of the OxEra TM Device at the Intensive Care Unit training centre of the Chris Hani Baragwanath Academic Hospital, Johannesburg, South Africa. This is a large academic facility affiliated with the University of the Witwatersrand. The protocol was approved by the University of Witwatersrand's Human Research Ethics Committee (HREC No: M210222). National Research Database Reference Number GP 202107013. Written informed consent was obtained from each participant ( Table 1 ).
Statistical Analysis: All continuous data were described using median and interquartile range (IQR) while categorical data were described using number (n) and percentage (%). Dependent data were compared using the Wilcoxon matched-pairs test (2 groups) or the Friedman ANOVA tests for more than 2 groups. A p -value < 0.05 was considered significant.
Sample Size: The sample size was based on the calculation of a single mean estimate. In the case of rebreathing a significant rise in ETCO 2 will occur [5] . This may be accompanied by a decrease in oxygen saturation [5] . We, therefore, used an ETCO 2 mean threshold value of 45 mmHg and a standard deviation of 6.3 mmHg. Using a 5% precision, we required a sample size of 30 participants.
Outcomes: The main outcome was to determine if there was a significant increase in ETCO 2 using a threshold of 45 mmHg or an increment of 6.3 mmHg for the study duration. Secondary and tertiary outcomes included changes in pulse oximetry saturation readings, blood pressure, respiratory rate (RR), HR, and pain and comfort scores for the duration of the study.

Results
Participant Description: The thirty participants had a median age of 30, with the youngest being 25 years of age and the oldest being 41 years of age. The median weight was 71.5 kg with an interquartile range from 61 to 80 kg. The median height measured was 170 cm with an interquartile range of 167-176 cm. Therefore, the median Body Mass Index (BMI) was 24.7 kg/m 2 , with interquartile ranges of 21.9-25.9 kg/m 2 .
Main Outcome: There was no significant difference in ETCO 2 from baseline until T9 at 2 h ( p = 0.13). No participant experienced an increase in measured ETCO 2 up to a value greater than 45 mmHg. No participant experienced an increase in measured ETCO 2 greater than 6.3 mmHg. The median increase in ETCO 2 ( ∆ ETCO 2 ) over the study period was 2 mmHg (IQR, 0-1). See Fig. 1 .
Pulse Oximetry (SpO 2 %): Sixteen (16 out of 30) participants had a SpO 2 % reading of 100% at baseline, while 14 participants had a value of between 94 and 99% at baseline. Thirteen (13/14) had an increase in SpO 2 % by 5 min on the OxEra TM and one (1/14) had an increase by 20 min.      Systolic Blood Pressure (SBP): There were no significant changes in SBP from baseline to 2 h (T9), p = 0.14. See Fig. 5 .
VAS Score: The VAS score had a significant increase from T0 to T9, p = 0.000. The worst median VAS score was 2 at T3, T4, and T5. This decreased to a median VAS score of 1 by T9. See Fig. 7 .   PAS Score: There was no significant increase in PAS scores from T0 to T9, p = 0.09. See Fig. 8 .
Comfort Score: There was a significant increase in comfort scores from T0 to T9, p = 0.000. The worst median comfort score was 2 at T4 and T5 (i.e., the comfort was worst on average at this stage). This decreased to a median comfort score of 1 by T7. See Fig. 9 .

Discussion
Safety: The main aim of this study was to assess the safety of the OxEra TM device concerning the risk of rebreathing. This safety aspect is key amongst many characteristics on which a CPAP system is selected. In our limited resource setting, safety, portability, comfort, ease of use, and the ability to reduce oxygen requirements are key [10] . The risk of rebreathing is a well-established risk and design features suggest the inclusion of a passive/ safety valve [11] . Capnography is a useful tool to detect changes in ETCO 2 that may be caused by rebreathing [9] . The clinical consequences of exposing patients to rebreathing and increased work of breathing must be avoided, and clinical studies are required to understand these issues [12] .
The main finding of our study showed no significant difference in ETCO 2 from baseline until the end of the study. No participant experienced an increase in ETCO 2 above the upper reference limit. In addition, no participant experienced an increase in ETCO 2 greater than the imprecision of the measurement device (capnography devices). This finding confirms the safety of the OxEra TM device concerning rebreathing.
Tolerance of OxEra TM device: Discontinuation of PEP will occur in a significant proportion of patients due to pain and discomfort. A recent study during the SARS CoV-2 pandemic demonstrated that 12% of patients on CPAP discontinued due to pain and discomfort [13] . A CPAP trial showed that 70-80% who were placed on CPAP continued, whereas 5-30% abandoned them. The reasons attributed to abandonment were mainly lacking benefit but also included mask discomfort, anxiety, pain, and noise [14] . In another study, 15% of the participants abandoned CPAP mainly due to its discomfort with the mask [15] .
A multi-variable approach to pain and discomfort may be superior to any one method of detection [16] . The normal physiological change in the cardiac system with PEP is a decrease in cardiac output and mean arterial pressure [17] .
Respiratory physiological changes of PEP are usually monitored in studies with invasive methods. These studies observed that the work of breathing is shown to be reduced in unhealthy patients with increases in PEP from as little as 5 cmH 2 O [18] . Healthy individuals are not meant to decrease the work of breathing. As expected in our healthy participants, there were no changes in the respiratory rate in the participants in the study. There were no significant changes in mean arterial pressure, systolic blood pressure, or diastolic blood pressure. Similarly, we did not find an increase in heart rate or respiratory rate. The lack of significant changes in these physiological markers suggest tolerance of the OxEra TM device.
Pain/discomfort: Pain and discomfort are notoriously difficult to assess in severe or critically ill patients [17] . Appropriate assessment of pain is key to its management [18] . Validated pain tools like NRS, also known as PAS, and the VAS are required to objectively assess comfort and pain [19] . There was no significant change in the PAS. The changes in the VAS score did not reach the threshold required to initiate acetaminophen or anti-inflammatory drugs, making them unlikely to result in the termination of CPAP therapy [20] . These changes are simply managed by reassurance and observation. The comfort score increased marginally, but once again, it did not reach the threshold for activating a formal pain assessment. These elevations in the VAS and comfort score occurred at positive pressure levels of 20 cmH 2 0. The combination of the lack of physiological changes of pain and the lack of significant indicators of pain using objective scoring systems suggest that the OxEra TM device was well tolerated on a positive pressure as high as 20cmH 2 0, and discontinuation due the pain or discomfort is unlikely.
Limitations: Although we used an imprecision documented in the literature, we did not measure this in the capnograph instrument used for the study. Secondly, we did not measure the positive pressure generated by the OxEra TM device in our subjects; however, this has been previously done for SAHPRA approval. Lastly, we could have improved on the average age of participants. An older population would have distributed the sample size to a greater general population.

Conclusion
The OxEra TM device is an innovative oxygen delivery device that has many benefits, especially in this era of COVID 19. Currently, it has SAPHRA approval to be used in the COVID 19 pandemic for emergency use.
The OxEra TM device demonstrated safety in terms of risk of rebreathing and was well tolerated up to a positive pressure of 20 cmH 2 0 in this clinical evaluation amongst healthy participants.
With approval for the safety of this device, the OxEra TM may have use in various fields of medicine involving respiratory diseases, specifically in resource and oxygen-limited settings.

Dissemination of results
The results of this study were presented as a Master of Medicine Report. The report will be displayed on a poster in the Witwatersrand University's School of Medicine, Bienniel Research Day on the 30th of September 2021.

Author contribution
Authors contributed as follow to the conception or design of the work; the acquisition, analysis, or interpretation of data for the work; and drafting the work or revising it critically for important intellectual content: MTJ contributed 70% and SVB, SO and JB contributed 10% each. All authors approved the version to be published and agreed to be accountable for all aspects of the work.

Declaration of Competing Interest
The authors declared no conflicts of interest.